{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T02:01:44Z","timestamp":1784512904830,"version":"3.55.0"},"reference-count":94,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T00:00:00Z","timestamp":1784419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disorder caused by biallelic loss-of-function mutations in the ADA2 gene (formerly CECR1). First described in 2014, DADA2 has emerged as a paradigm for monogenic vasculitis, bridging the gap between primary immunodeficiencies and systemic vasculitides. The disease is characterized by a remarkably broad clinical spectrum encompassing early-onset lacunar stroke, systemic vasculitis resembling polyarteritis nodosa (PAN), hematologic abnormalities ranging from pure red cell aplasia to pancytopenia, humoral immunodeficiency, and variable lymphoproliferation. ADA2, predominantly secreted by myeloid cells, serves dual functions as a growth factor for endothelial cells and a modulator of extracellular adenosine metabolism. Its deficiency leads to a proinflammatory state driven by macrophage dysregulation, excessive tumor necrosis factor (TNF) production, neutrophil extracellular trap (NET) formation, and endothelial dysfunction. The genotype\u2013phenotype correlation is complex, with certain mutations predisposing to vasculitic versus hematologic-predominant phenotypes. Emerging evidence further links ADA2 deficiency to cellular senescence and inflammaging pathways, suggesting a connection between monogenic vasculitis and aging-related biological mechanisms. Anti-TNF therapy has revolutionized disease management, achieving sustained remission in the majority of vasculitic manifestations. Hematopoietic stem cell transplantation (HSCT) offers a definitive cure for severe hematologic disease, while gene therapy approaches are under active investigation. This review synthesizes current knowledge on the immunopathogenesis, clinical heterogeneity, genotype\u2013phenotype correlations, multi-omics insights, and evolving precision therapeutic strategies for DADA2, positioning it as an instructive model for understanding monogenic immune vasculopathy. Despite this progress, fundamental questions remain\u2014including the relative contribution of ADA2 enzymatic versus growth factor functions to disease pathogenesis, the mechanisms underlying tissue-specific vulnerability, the basis of differential treatment responsiveness, and the identity of genetic and environmental modifiers that determine phenotypic heterogeneity\u2014that define the frontier of current DADA2 research. This review critically evaluates both established knowledge and persistent uncertainties, positioning DADA2 as an instructive model for the study of monogenic immune vasculopathy.<\/jats:p>","DOI":"10.3390\/biom16071057","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:47:32Z","timestamp":1784508452000},"page":"1057","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DADA2 as a Model of Monogenic Immune Vasculopathy: From Immunopathogenesis to Precision Therapeutics"],"prefix":"10.3390","volume":"16","author":[{"given":"Hao","family":"Peng","sequence":"first","affiliation":[{"name":"Laboratory Center, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin 541199, China"},{"name":"Genetics and Cellular Engineering Group, Research Unit Signaling and Translation, Helmholtz Zentrum Munich, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxia","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory Center, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin 541199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chune","family":"Mo","sequence":"additional","affiliation":[{"name":"Laboratory Center, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin 541199, China"},{"name":"Laboratory Center, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, Guilin Medical University, Guilin 541199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bihui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Second Affiliated Hospital of Guilin Medical University, Guilin 541199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minglin","family":"Ou","sequence":"additional","affiliation":[{"name":"Laboratory Center, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin 541199, China"},{"name":"Laboratory Center, Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, Guilin Medical University, Guilin 541199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/art.37715","article-title":"2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides","volume":"65","author":"Jennette","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/s41584-025-01250-9","article-title":"The pathogenesis, clinical presentations and treatment of monogenic systemic vasculitis","volume":"21","author":"Aksentijevich","year":"2025","journal-title":"Nat. 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